Volker Heussler

Mutagenesis of PbICP, a cysteine protease inhibitor of Plasmodium berghei

Principle Investigator:

PD Dr. Volker Heussler, Bernhard-Nocht-Institute (BNI) 

Background:

Cysteine proteases play a crucial role in the infection of the liver by Plasmodium sporozoites, in parasite development in liver cells and in the liberation of the fully developed liver merozoites. Additionally, intra- and extracellular Plasmodium parasites might be exposed to host cell proteases. Therefore, a tight and protease-specific regulation must be critical for the survival of the parasites and it is likely that Plasmodium parasites have evolved mechanisms to counteract proteolytic digestion. Short-term regulation of parasite as well as host proteases can be mediated by specific parasite-derived inhibitors. A prominent example is chagasin, which is expressed by Trypanosoma cruzi and was the first identified member of a new superfamily of reversible, tight-binding cysteine protease inhibitors. Chagasin-like inhibitors (also termed ICPs for inhibitor of cysteine proteases) are suggested to regulate both endogenous parasite-derived cysteine proteases (T. brucei, T. cruzi, P. falciparum, E. histolytica) and/or host cell proteases (L. mexicana, P. aeruginosa, P. falciparum). We have identified a chagasin-like inhibitor of the rodent parasite P. berghei and named it PbICP for P. berghei Inhibitor of Cysteine Proteases. PbICP consists of a C-terminal chagasin-like domain and a long N-terminal extension domain with an unknown function. Experiments with recombinantly expressed PbICP revealed that the inhibitor activity is maintained after deletion of the N-terminal extension region. In contrast to chagasin, PbICP does not inhibit cathepsin B but, similar to chagasin, it is a very potent inhibitor of human cathepsin L and papain.

Due to the interdisciplinary nature of the project, the graduate student will work in a joint appointment between the labs of PD Dr. Volker Heussler (BNI), Prof. Rolf Hilgenfeld (Uni Lübeck and Prof. Christian Betzel (Uni Hamburg).

Homepage Heussler

http://www.bni-hamburg.de/

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